A Convergent Synthetic Approach to the Nucleoside-Type Liposidomycin Antibiotics

Article abstract of DOI:10.1021/ol0355074

(Matrix presented) A synthetic approach toward the liposidomycins, a family of complex nucleoside-type antibiotics, is reported based on the synthesis of epoxy-amides derived from the reaction of sulfur ylides with the uridyl aldehyde derivative 6. To thi

Full text of DOI:10.1021/ol0355074

ORGANIC
LETTERS
2003
Vol. 5, No. 21
3927-3930
A Convergent Synthetic Approach to the
Nucleoside-Type Liposidomycin
Antibiotics
Francisco Sarabia,* Laura Mart´ın-Ortiz, and F. Jorge Lo´pez-Herrera†
Departamento de Bioqu´ımica, Biolog´ıa Molecular y Qu´ımica Orga´nica,
Facultad de Ciencias, UniVersidad de Ma´laga, 29071-Ma´laga, Spain
frsarabia@uma.es
Received August 8, 2003
ABSTRACT
A synthetic approach toward the liposidomycins, a family of complex nucleoside-type antibiotics, is reported based on the synthesis of
epoxy-amides derived from the reaction of sulfur ylides with the uridyl aldehyde derivative 6. To this end, the epoxy-amide derivative of
indoline 14 was stereoselectively prepared and, after treatment with DDQ, transformed into the corresponding N-indole epoxyamide 15. The
indole 15 provides ready access to a variety of structures related to the diazepanone core present in the liposidomycins by reaction with a
variety of amines.
The growing emergence of drug resistance by specific
bacterial strains to current antibiotics is becoming a problem
of profound importance around the world, and has prompted
the need for new antibiotics with novel mechanisms of
action.1 Of special concern have been the appearance of
Staphylococcus aureus bacterial strains resistant to antibiotics
such as the â-lactams and vancomycin, both inhibitors of
the biosynthesis of the peptidoglycan cell wall in bacteria.
In the meantime, new antibiotics, either from synthetic or
natural sources, are continuously emerging.2 Among them,
the liposidomycins, isolated from Streptomyces griseosporeus,3
constitute a new class of complex nucleoside-type antibiotics,
which are structurally and biologically related to other uridyl
peptide antibiotics such as the muraymycins, tunicamycins,
mureidomycins, pacidamycins, napsamycins, and FR-
900493.4 Particularly, the liposidomycins comprise at least
12 active members whose major components are liposido-
mycin A (1), B (2), and C (3) (Figure 1).5
The antibiotic activity exhibited by the liposidomycins is
due to their inhibition of the phospho-N-acetyl-muramoyl-
pentapeptide-transferase (translocase I) enzyme, which is
responsible for the first step of the lipid cycle involved in
the biosynthesis of peptidoglycan in bacteria.6 Other types
of related antibiotics, such as the tunicamycins and moeno-
mycin, display a similar mechanism of action; however, the
liposidomycins have shown comparatively higher potency
† Deceased.
(1) Isono, K. J. Antibiot. 1988, 41, 1711-1739.
(2) (a) Chu, D. T. W.; Plattner, J. J.; Katz, L. J. Med. Chem. 1996, 39,
3853-3874. (b) Su¨ssmuth, R. D. ChemBioChem 2002, 3, 295-298. (c)
Gao, Y. Nat. Prod. Rep. 2002, 19, 100-107. (d) Nicolaou, K. C.; Boddy,
C. N. C.; Bra¨se, S.; Winssinger, N. Angew. Chem., Int. Ed. 1999, 38, 2096-
2152.
(4) Kimura, K.-i.; Bugg, T. D. H. Nat. Prod. Rep. 2003, 20, 252-273.
(5) (a) Ubukata, M.; Isono, K.; Kimura, K.-I.; Nelson, C. C.; McCloskey,
J. A. J. Am. Chem. Soc. 1988, 110, 4416-4417. (b) Ubukata, M.; Kimura,
K.-I.; Isono, K.; Nelson, C. C.; Gregson, J. M.; McCloskey, J. A. J. Org.
Chem. 1992, 57, 6392-6403.
(6) Struve, W. G.; Sinha, R. K.; Neuhaus, F. C.; Prime, M. S.
Biochemistry 1966, 5, 82-93.
(3) (a) Isono, K.; Uramoto, M.; Kusakabe, H.; Kimura, K.-I.; Izaki, K.;
Nelson, C. C.; McCloskey, J. A. J. Antibiot. 1985, 38, 1617-1621. (b)
Kimura, K.-I.; Kagami, S.; Ikeda, Y.; Takahashi, H.; Yoshihama, M.;
Kusakabe, H.; Osada, H.; Isono, K. J. Antibiot. 1998, 51, 640-646. (c)
Kimura, K.-I.; Ikeda, Y.; Kagami, S.; Yoshihama, M.; Ubukata, M.; Esumi,
Y.; Osada, H.; Isono, K. J. Antibiot. 1998, 51, 647-654.
10.1021/ol0355074 CCC: $25.00 © 2003 American Chemical Society
Published on Web 09/12/2003

Scheme 1. Retrosynthetic Analysis
Figure 1. Molecular structures of liposidomycins.
in vitro with an ID50 of 0.03 µg/mL.7 In addition to these
prominent biological properties, the liposidomycins offer
attractive structural features, characterized by a 3,6,7-
trisubstituted-1,4-dimethyldiazepan-2-one system, which is
linked to a uridine nucleoside moiety through a carbon
bridge. Located at this carbon, we find a hydroxyl group,
which is linked to a 5-deoxy-5-amino-ribofuranosyl residue
by a glycosidic bond.8 Despite the liposidomicins general
structure having been previously elucidated, the absolute
configurations of the indicated chiral centers in Figure 1,
located in the diazepanone ring and in the exo-OH domains,
remain unnassigned.9 Nevertheless, recent synthetic studies
conducted by Knapp et al. have suggested that the configura-
tions at C-5′ and C-6′ are (S).10 Similarly, configurations at
C-2′′′ and C-3′′′ have been tentatively established as 2′′′S
and 3′′′S through further synthetic studies.11 All these
structural features, in conjunction with the biological proper-
ties of liposidomycins, compelled us to embark on a program
aimed at the total synthesis of these natural nucleosides. In
the present paper, we wish to report the first synthetic studies
directed toward the synthesis of the diazepanone core
structure of the liposidomycins, based on the chemistry of
sulfur ylides, which is well suited to the preparation of not
only the natural antibiotics but also of potentially bioactive
analogues.12
diazepanone ring. According to this, the liposidomycins
would initially be disconnected at the glycosydic site to
obtain the corresponding donor derived from 5-deoxy-5-
amino-D-ribose and the acceptor compound 4. The second
major retrosynthetic disconnection is at the N1-C2 bond of
compound 4 to generate epoxyamide 5, which would give
rise to the corresponding diazepanone derivative 4 via an
intramolecular 7-exo-tet cyclization reaction. Finally, ep-
oxyamide 5 could be prepared from the corresponding
aldehyde 6 by reaction with the sulfur ylide 7, which would
contain the suitable functionality present in the diazepanone
ring.
Our initial synthetic studies were focused on a model
compound to prove the efficiency of the designed strategy.
Therefore, we commenced with the synthesis of the sulfo-
nium salt 9 by conventional methods.13 The reaction of
aldehyde 614 with the corresponding sulfur ylide derived from
9 was performed by two different procedures: (a) the one-
phase method, in which the ylide was previously prepared,
and (b) the two-phase method,15 in which the ylide was
generated in situ by treatment of 9 with an aqueous sodium
hydroxide solution. In both cases, the epoxide 10 was
obtained in 67% yield and high diastereoselectivity, ap-
1
proximately 90:10 according to the H NMR spectra. The
configurations for the new two chiral centers of the oxirane
Scheme 1 outlines briefly the retrosynthetic analysis of
the liposidomycin core, using sulfur ylides to construct the
(12) Analogues of the liposidomycins: (a) Dini, C.; Collete, P.; Drochon,
N.; Guillot, J. C.; Lemoine, G.; Mauvais, P.; Aszodi, J. Bioorg. Med. Chem.
Lett. 2000, 10, 1839-1843. (b) Dini, C.; Drochon, N.; Feteanu, S.; Guillot,
J. C.; Peixoto, C.; Aszodi, J. Bioorg. Med. Chem. Lett. 2001, 11, 529-
531. (c) Dini, C.; Drochon, N.; Guillot, J. C.; Mauvais, P.; Walter, P.;
Aszodi, J. Bioorg. Med. Chem. Lett. 2001, 11, 533-536. (d) Dini, C.; Didier-
Laurent, S.; Drochon, N.; Feteanu, S.; Guillot, J. C.; Monti, F.; Uridat, E.;
Zhang, J.; Aszodi, J. Bioorg. Med. Chem. Lett. 2002, 12, 1209-1213.
(13) Lo´pez Herrera, F. J.; Sarabia Garc´ıa, F.; Heras Lo´pez, A.; Pino
Gonza´lez, M. S. J. Org. Chem., 1997, 62, 6056-6059 and references therein.
(14) Danishefsky, S. J.; DeNinno, S. L.; Chen, S.-h.; Boisvert, L.;
Barbachyn, M. J. Am. Chem. Soc. 1989, 111, 5810-5818.
(7) (a) Kimura, K.-I.; Miyata, N.; Kawanishi, G.; Kamio, Y.; Izaki, K.;
Isono, K. Agric. Biol. Chem. 1989, 53, 1811-1815. (b) Muroi, M.; Kimura,
K.-I.; Osada, H.; Inukai, M.; Takatsuki, A. J. Antibiot. 1997, 50, 103-104.
(c) Kimura, K.-I.; Ikeda, Y.; Kagami, S.; Yoshihama, M.; Suzuki, K.; Osada,
H.; Isono, K. J. Antibiot. 1998, 51, 1099-1104.
(8) Knapp, S.; Morriello, G. J.; Doss, G. A. Tetrahedron Lett. 2002, 43,
5797-5800 and references therein.
(9) Knapp, S.; Morriello, G. J.; Nandan, S. R.; Emge, T. J.; Doss, G.
A.; Mosley, R. T.; Chen, L. J. Org. Chem. 2001, 66, 5822-5831.
(10) Knapp, S.; Morriello, G. J.; Doss, G. A. Org. Lett. 2002, 4, 603-
606.
(11) Nakajima, N.; Isobe, T.; Irisa, S.; Ubukata, M. Heterocycles 2003,
59, 107-113.
(15) Lo´pez Herrera, F. J.; Pino Gonza´lez, M. S.; Sarabia Garc´ıa, F.; Heras
Lo´pez, A.; Ortega Alca´ntara, J. J.; Pedraza Cebria´n, M. G. Tetrahedron:
Asymmetry 1996, 7, 2065.
3928
Org. Lett., Vol. 5, No. 21, 2003

Scheme 2. First Synthetic Approach
Scheme 3. Synthesis of the Diazepanone Ring
ring were established based on synthetic and theoretical
studies.16 Unfortunately, this straightforward strategy pre-
sented two important drawbacks. One was the lack of
reliability upon scale-up of the reaction sequence. In fact,
the yields dropped considerably when the reactions were
carried out on multigram scale. Also, attempts to produce
the diazepanone ring by intramolecular cyclization from
alcohol 11 to give the corresponding cyclic ether or by
treatment of 11 with amines under Mitsunobu conditions to
give the corresponding cyclic amines were unsuccessful
(Scheme 2).
In light of these discouraging results, we decided to modify
the initial synthetic strategy by creating a new more
convergent route. Accordingly, we decided to use the
indoline epoxy-amide derivative 14 as a valuable key
intermediate in the synthesis due to its facile oxidation17 to
the corresponding indole derivative 15, which in turn can
react with nucleophiles,18 offering an excellent opportunity
for the construction of the diazepanone ring via reaction with
bidentate nucleophiles.
Thus, the reaction of 6 with the sulfonium salt 13, prepared
from sulfide 12 by treatment with the Meerwein salt, afforded
epoxy-amide 14 in high yield and stereoselectivity. Further-
more, this reaction was achieved in multigram scale with
no appreciable loss in yield. The oxidation of the indoline
amide 14 with DDQ furnished the corresponding indole
derivative 15 in 76% yield. To our delight, when indole 15
was treated with N,N′-dimethyl-1,3-propanediamine under
mild conditions the corresponding diazepanone derivative
16 was smoothly obtained in good yield (Scheme 3).
This encouraging result prompted us to extend the reaction
to other nucleophiles to provide access to intermediates for
the eventual incorporation into a synthetic scheme capable
of reaching the target natural diazepanone moiety contained
in the liposidomycins. Thus, simple diamines were reacted
with indole 15, to obtain cyclic compounds 17-19. On the
basis of these studies, it was concluded that an increase in
the steric hindrance surrounding the nucleophilic nitrogens
necessitated the use of forcing reaction conditions, with
respect of the case of N,N′-dimethyl-1,3-propanediamine. It
is interesting to note that for asymmetric diamines, the
corresponding cyclic compound, 18, was obtained in com-
plete regioselectivity. On the other hand, the six-membered
analogue of the diazepanone derivative was achieved in good
yield when 15 was reacted with N,N′-dimethyl-1,2-ethanedi-
amine.
The extension of these studies to more complex amines,
to construct the diazepanone ring contained in the natural
liposidomycins, was similarly screened. Toward such a goal,
a set of complex secondary amines 20-2319,20 were prepared
and reacted with the epoxy indole 15 to obtain epoxy-amides
24-27, respectively. Thus, it was observed that the reaction
showed a high sensitivity toward steric effects, as was
demonstrated for bulky amines in which no reaction or
decomposition products were formed (see Supporting Infor-
mation for details). With respect to the electron-withdrawing
effects introduced in amines with an amide group (amine
23), the reaction does not seem to be affected, given the
reasonable yield obtained for the desired product, amide 27
(68%).
(16) Chemically, Sharpless epoxidation of the allylic alcohol obtained
by reaction of methyl 2,3-O-isopropylidene-â-D-ribo-pentonodialdo-1,4-
furanoside with Ph3PdCHCO2Me, followed by reduction with DIBAL-H,
with (+)-DET and (-)-DET, respectively, yielded the corresponding
epoxides, which were compared with the one obtained from the epoxy
alcohol obtained via the sulfur ylides. This result allowed one to conclude
that the epoxide obtained via the sulfur ylides possessed a 2R,3S config-
uration at the oxirane ring. In addition, theoretical calculations executed
on the starting aldehyde 6 revealed a conformational preference in which
the re face of the aldehyde appeared to be the more accessible for the ylide
attack, which is in agreement with the configuration found for the above
epoxy amide obtained from methyl 2,3-O-isopropylidene-â-D-ribo-pen-
tonodialdo-1,4-furanoside (see Supporting Information for details).
(17) de Oliveira Baptista, M. J. V.; Barrett, A. G. M.; Barton, D. H. R.;
Girijavallabhan, M.; Jennings, R. C.; Kelly, J.; Papadimitriou, V. J.; Turner,
J. V.; Usher, N. A. J. Chem. Soc., Perkin Trans. 1 1977, 1477-1500.
(18) Nicolaou, K. C.; Zhong, Y.-L.; Baran, P. S.; Jung, J.; Choi, H.-S.;
Yoon, W. H. J. Am. Chem. Soc. 2002, 124, 2202-2211.
(19) Valpuesta-Ferna´ndez, M.; Durante Lanes, P.; Lo´pez Herrera, F. J.
Tetrahedron Lett. 1995, 36, 4681-4684.
(20) Righi, G.; Pescarote, G.; Bonadies, F.; Bonini, C. Tetrahedron 2001,
57, 5649-5656.
Org. Lett., Vol. 5, No. 21, 2003
3929

reaction with m-CPBA to obtain epoxides 29a/29b in a 1:1
mixture of inseparable stereisomers in a reasonable yield.
The mixture of diepoxides 29 was then treated with an
aqueous solution of methylamine to obtain the corresponding
cyclic derivatives 30a/30b by a double oxirane opening
process, probably initiated by an intermolecular opening
reaction of methylamine with the terminal epoxide, followed
by a second intramolecular opening of the epoxy-amide by
the resulting secondary amine in a regioselective manner.
In conclusion, we report a new approach to the liposido-
mycins aimed at delivering not only the natural compounds
but also analogues thereof. Initial results have proved the
feasibility and efficiency of our synthetic approach toward
the diazepanone ring system present in this class of complex
nucleoside antibiotics. Our future synthetic endeavors include
the construction of the real system contained in liposido-
mycins based on the reported strategy, followed by the
linkage of the 5-deoxy-5-aminoribose unit via a glycosylation
reaction. Both synthetic transformations are currently being
investigated.
Scheme 4. Construction of Functionalized Diazepanone Rings
Acknowledgment. This work was financially supported
by Fundacio´n Ramo´n Areces and the Direccio´n General de
Investigacio´n (ref. BQU2001-1576). L.M.O. thanks the
Direccio´n General de Universidades e Investigacio´n, Con-
sejer´ıa de Educacio´n y Ciencia, Junta de Andaluc´ıa for a
scholarship. We thank Dr. J. I. Trujillo from Pfizer (St. Louis,
MO) and J. Mart´ın-Ortiz from the University of Malaga for
assistance in the preparation of this manuscript and in the
molecular modeling studies, respectively. We thank Unidad
de Espectroscop´ıa de Masas de la Universidad de Sevilla
for mass spectroscopy assistance.
It is worthy to mention that compounds 24-27 possess
suitable functionality amenable to the introduction of the
required groups to complete the diazepanone ring. Initial
attempts to accomplish the synthesis of the diazepanone
system contained in the natural product were performed
beginning from the acyclic precursors 24-27. However, none
of the numerous attempted methods proved to be effective
in the construction of such a diazepanone ring.
According to Scheme 4, a second possible strategy toward
a functionalized diazepanone ring was pursued. In this new
route, the allyl amide precursor 28, prepared from indole 15
by reaction with allylamine, was subjected to an epoxidation
Supporting Information Available: Experimental pro-
cedures and spectroscopic data for new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL0355074
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Org. Lett., Vol. 5, No. 21, 2003